Huntington's disease (HD) is a devastating neurodegenerative disease for which there is currently no therapy proven to delay onset or to slow progression of the disease. The development of therapies is slowed by an uncertain understanding of disease mechanisms and by the limited availability of biomarkers which could be used to monitor the effects of therapies in all phases of clinical trials. In this application w propose to use metabolomic approaches to better understand pathophysiology and to discover potential therapeutic targets and biomarkers. We have extensive data demonstrating that HD progressively affects a variety of biochemical pathways in plasma from patients beginning presymptomatically. Small molecules in the tryptophan, tyrosine, purine and redox pathways have particular potential as biomarkers. However, it is uncertain exactly how they reflect peripheral, systemic, or CNS manifestations of HD, information essential to defining their usefulness as markers. To help decipher whether the peripheral metabolomic changes we have observed originate from the brain, the entire body, or only from blood, we propose to use cerebrospinal fluid (CSF) and plasma from the same patients and compare and contrast their metabolomic signatures. We will also compare these results to metabolomic changes in postmortem HD brain. Our goal is to understand the inter-relationships of the plasma and CSF metabolomes and the overlap of these with the brain metabolome and to identify clinically relevant plasma and CSF markers of disease progression or response to therapy.